This invention relates to a process for the substantially regioselective acylation and alkylation of the 1-amino group of 4-O-substituted 2-deoxystreptamine-containing aminoglycosides effected by zinc salts. Examples of 4-O-substituted 2-deoxystreptamine-containing aminoglycosides used in the process of the present invention include the antibiotics apramycin (see U.S. Pat. Nos. 3,691,279, 3,853,709 and 3,876, 767): ##STR1## and nebramine: ##STR2##
The nomenclature of the above formula of apramycin is simplified by the following numbering system in which the carbons of the 2-deoxystreptamine moiety are numbered 1 through 6, the carbons of the octose moiety are numbered with a single prime, 1'-8', and the carbons of the hexose moiety are numbered with a double prime, 1"-6". ##STR3##
Analogously, the aprosaminide aminoglycosides referred to in this invention have the same numbering system as apramycin with respect to the octose and 2-deoxystreptamine moieties: ##STR4##
The numbering system for the pseudodisaccharides referred to in this invention, such as nebramine, has the carbons of the 2-deoxystreptamine moiety numbered 1-6, the same as for apramycin and the aprosaminides, but the hexose carbons are numbered with a single prime, 1'-6'. ##STR5##
N-substituted derivatives of aminoglycoside antibiotics have been of great interest because many exhibit much broader antibacterial activity than do the parent antibiotics. Methods for selective N-substitution of aminoglycosides are, therefore, in great demand. The use of transition metal cations to selectively protect certain amino groups in aminoglycoside antibiotics from acylation has been reported by the following groups of workers:
T. L. Nagabhushan, Abstr. 9th Int. Symp. Carbohyd. Chem., papers B36 and B37 (1978); T. L. Nagabhushan, et al., J. Am. Chem. Soc., 100, 5253 (1978); PA1 T. L. Nagabhushan, W. N. Turner and A. Cooper, U.S. Pat. Nos. 4,136,254 (1979) and 4,230,847 (1980). PA1 S. Hanessian and G. Patil, Tet. Letters, 1031 and 1035 (1978). PA1 R. E. Carney and J. B. McAlpine, Abstr. 175th ACS Meeting, Carb. 46 (1978). PA1 R. E. Carney and S. Hanessian, U.S. Pat. No. 4,214,077 (1980). PA1 T. Tsuchiya, Y. Takagi and S. Umezawa, Tet. Letters, 4951 (1979). PA1 (1) combining the above aminoglycoside with about two to about six molar equivalents of a zinc salt of the formula: EQU Zn(X).sub.2 PA1 Zn(acetate).sub.2 PA1 Zn(propionate).sub.2 PA1 Zn(hexanoate).sub.2 PA1 Zn(2-ethylhexanoate).sub.2 PA1 Zn(benzoate).sub.2 PA1 Zn(octanoate).sub.2 PA1 Zn(neodecanoate).sub.2.
Although a number of different transition metal cations were examined in these studies, the site of acylation did not generally depend on the particular cation used.
Until now, the prior art has not disclosed a direct acylation of the 1-amino group of aminoglycoside antibiotics. In contrast to the results obtained in the prior art, we have been able to directly synthesize 1-N-substituted derivatives of 4-O-substituted 2-deoxystreptamine aminoglycosides in a single reaction, using zinc salts to substantially control the site of derivatization.
A further aspect of this invention involves the biologically active 1-N-substituted derivatives of apramycin, substituted apramycins and alkyl aprosaminides which are synthesized by the process of this invention.